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Objectives Oligometastatic colorectal cancer benefits of locoregional treatments but data concerning microwave ablation (MWA) are limited and interactions with systemic therapy are still debated. The aim of this study is to evaluate safety and effectiveness of Thermosphere™ MWA (T-MWA) of colorectal liver metastases (CLM) and factors affecting local tumor progression-free survival (LTPFS). Methods In this multi-institutional retrospective study (January 2015–September 2019), patients who underwent T-MWA for CLM were enrolled. Complications according to SIR classification were collected, primary efficacy and LTP were calculated. Analyzed variables included CLM size at diagnosis and at ablation, CLM number, ablation margins, intra-segment progression, chemotherapy before ablation (CBA), variations in size (ΔSDIA-ABL), and velocity of size variation (VDIA-ABL) between CLM diagnosis and ablation. Uni/multivariate analyses were performed using mixed effects Cox model to account for the hierarchical structure of data, patient/lesions. Results One hundred thirty-two patients with 213 CLM were evaluated. Complications were reported in 6/150 procedures (4%); no biliary complications occurred. Primary efficacy was achieved in 204/213 CLM (95.7%). LTP occurred in 58/204 CLM (28.4%). Six-, twelve-, and eighteen-month LTPFS were 88.2%, 75.8%, and 69.9%, respectively. At multivariate analysis, CLM size at ablation (p = 0.00045), CLM number (p = 0.046), ablation margin p = 0.0035), and intra-segment progression (p DIA-ABL (p = 0.63) and VDIA-ABL (p = 0.38) did not affect LTPFS. Ablation margins in the chemo-naïve group were larger than those in the CBA group (p Conclusion T-MWA is a safe and effective technology with adequate LTPFS rates. Intra-segment progression is significantly linked to LTPFS. CBA does not affect LTPFS. Anticipating ablation before chemotherapy may take the advantages of adequate tumor size with correct ablation margin planning. Key Points • Thermosphere™-Microwave ablation is a safe and effective treatment for colorectal liver metastases with no registered biliary complications in more than 200 ablations. • Metastases size at time of ablation, intra-segment progression, and minimal ablation margin • Chemotherapy before ablation modifies kinetics growth of the lesions but deteriorates ablation margins and does not significantly impact local tumor progression-free survival.